Biomarker of neutrophil extracellular traps is associated with deep-seated infections and predicts mortality and cardiovascular morbidity in commensal streptococcal bacteremia

Kuo, Yu-Min; Yang, Lin; Lee, Ming-Jui; Chen, Jeng‐Wei; Hsu, Cheng Hsing; Huang, Teng Yi; Chen, Jen-Hao; Tzeng, Shiang-Jong; Chiu, Yen‐Ling; Wang, Shih-Rong; Chia, Jean-San; Hsieh, Song-Chou; Jung, Chiau Jing

doi:10.1016/j.jmii.2022.04.009

Cited by 3 publications

(1 citation statement)

References 22 publications

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“…Thus, the regulation of NET formation with regard to location, timing, and magnitude is critical to efficient microbial containment while limiting host damage ( 43 ). One of the most severe examples of NET injury is immunothrombosis leading to multiorgan failure and death in sepsis ( 44 , 45 ). In fact, patients with sepsis often face high mortality once the inflammatory process has begun with limited treatment options to change outcomes.…”

Section: Discussionmentioning

confidence: 99%

Neonatal NET-Inhibitory Factor improves survival in the cecal ligation and puncture model of polymicrobial sepsis by inhibiting neutrophil extracellular traps

et al. 2023

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IntroductionNeutrophil extracellular traps (NETs) clear pathogens but may contribute Q8 pathogenically to host inflammatory tissue damage during sepsis. Innovative therapeutic agents targeting NET formation and their potentially harmful collateral effects remain understudied.MethodsWe investigated a novel therapeutic agent, neonatal NET-Inhibitory Factor (nNIF), in a mouse model of experimental sepsis – cecal ligation and puncture (CLP). We administered 2 doses of nNIF (1 mg/ kg) or its scrambled peptide control intravenously 4 and 10 hours after CLP treatment and assessed survival, peritoneal fluid and plasma NET formation using the MPO-DNA ELISA, aerobic bacterial colony forming units (CFU) using serial dilution and culture, peritoneal fluid and stool microbiomes using 16S rRNA gene sequencing, and inflammatory cytokine levels using a multiplexed cytokine array. Meropenem (25 mg/kg) treatment served as a clinically relevant treatment for infection.ResultsWe observed increased 6-day survival rates in nNIF (73%) and meropenem (80%) treated mice compared to controls (0%). nNIF decreased NET formation compared to controls, while meropenem did not impact NET formation. nNIF treatment led to increased peritoneal fluid and plasma bacterial CFUs consistent with loss of NET-mediated extracellular microbial killing, while nNIF treatment alone did not alter the peritoneal fluid and stool microbiomes compared to vehicle-treated CLP mice. nNIF treatment also decreased peritoneal TNF-a inflammatory cytokine levels compared to scrambled peptide control. Furthermore, adjunctive nNIF increased survival in a model of sub-optimal meropenem treatment (90% v 40%) in CLP-treated mice.DiscussionThus, our data demonstrate that nNIF inhibits NET formation in a translationally relevant mouse model of sepsis, improves survival when given as monotherapy or as an adjuvant with antibiotics, and may play an important protective role in sepsis.

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Section: Discussionmentioning

confidence: 99%

Neonatal NET-Inhibitory Factor improves survival in the cecal ligation and puncture model of polymicrobial sepsis by inhibiting neutrophil extracellular traps

et al. 2023

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Neutrophil extracellular traps in homeostasis and disease

Wang,

Kim,

Lei

et al. 2024

Sig Transduct Target Ther

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Neutrophil extracellular traps (NETs), crucial in immune defense mechanisms, are renowned for their propensity to expel decondensed chromatin embedded with inflammatory proteins. Our comprehension of NETs in pathogen clearance, immune regulation and disease pathogenesis, has grown significantly in recent years. NETs are not only pivotal in the context of infections but also exhibit significant involvement in sterile inflammation. Evidence suggests that excessive accumulation of NETs can result in vessel occlusion, tissue damage, and prolonged inflammatory responses, thereby contributing to the progression and exacerbation of various pathological states. Nevertheless, NETs exhibit dual functionalities in certain pathological contexts. While NETs may act as autoantigens, aggregated NET complexes can function as inflammatory mediators by degrading proinflammatory cytokines and chemokines. The delineation of molecules and signaling pathways governing NET formation aids in refining our appreciation of NETs’ role in immune homeostasis, inflammation, autoimmune diseases, metabolic dysregulation, and cancer. In this comprehensive review, we delve into the multifaceted roles of NETs in both homeostasis and disease, whilst discussing their potential as therapeutic targets. Our aim is to enhance the understanding of the intricate functions of NETs across the spectrum from physiology to pathology.

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Neutrophil Extracellular Traps and Neutrophil-Derived Extracellular Vesicles: Common Players in Neutrophil Effector Functions

Pfister

2022

Diagnostics

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Neutrophil granulocytes are a central component of the innate immune system. In recent years, they have gained considerable attention due to newly discovered biological effector functions and their involvement in various pathological conditions. They have been shown to trigger mechanisms that can either promote or inhibit the development of autoimmunity, thrombosis, and cancer. One mechanism for their modulatory effect is the release of extracellular vesicles (EVs), that trigger appropriate signaling pathways in immune cells and other target cells. In addition, activated neutrophils can release bactericidal DNA fibers decorated with proteins from neutrophil granules (neutrophil extracellular traps, NETs). While NETs are very effective in limiting pathogens, they can also cause severe damage if released in excess or cleared inefficiently. Since NETs and EVs share a variety of neutrophil molecules and initially act in the same microenvironment, differential biochemical and functional analysis is particularly challenging. This review focuses on the biochemical and functional parallels and the extent to which the overlapping spectrum of effector molecules has an impact on biological and pathological effects.

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Biomarker of neutrophil extracellular traps is associated with deep-seated infections and predicts mortality and cardiovascular morbidity in commensal streptococcal bacteremia

Cited by 3 publications

References 22 publications

Neonatal NET-Inhibitory Factor improves survival in the cecal ligation and puncture model of polymicrobial sepsis by inhibiting neutrophil extracellular traps

Neonatal NET-Inhibitory Factor improves survival in the cecal ligation and puncture model of polymicrobial sepsis by inhibiting neutrophil extracellular traps

Neutrophil extracellular traps in homeostasis and disease

Neutrophil Extracellular Traps and Neutrophil-Derived Extracellular Vesicles: Common Players in Neutrophil Effector Functions

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